In vertebrates, the immune system comprises the innate immune system and the adaptive immune system. Whereas the innate immune response recognizes pathogens in a non-specific way, for example through pattern-associated molecular patterns that distinguish pathogens from host molecules, the adaptive immune system is directed to specific antigens. Specificity of the adaptive immune response is taught by interaction with antigens, which are presented as a complex with major histocompatibility molecules (MHC) to adaptive immune cells. Several T cell subgroups can be activated by antigen presentation.
Interaction of the naïve T cell with the MHC complex requires interaction with CD4 or CD8 in addition to binding of the antigen by the T cell receptor (TCR). Class I MHC can be expressed on nearly every nucleated cell of the body, and it interacts with CD8, which is predominantly expressed on the cytotoxic class of T cells. These cells can induce the death of the cells presenting the antigen that resulted in the activation of the cell, so they are heavily regulated to prevent tissue damage. Activation of cytotoxic T cells requires strong MHC complex signal or additional activation provided by helper T cells. Helper T cells are characterized by CD4 expression, so they interact with the class II MHC. While these cells have no ability to kill cells carrying the antigen that resulted in its activation, these cells manage the immune response mounted by the antigen. Activation of naïve helper T cells results in the release of cytokines that can activate antigen-presenting cells or activate cytotoxic T cells. For example, Th1 or Th2 helper T cells enhance immune responses to different types of antigens. A Th1 response, which is characterized by the release of interferon-γ (IFNγ), leads to the activation of phagocytes, cytotoxic T cells, and the release of various cytokines in response to an antigen. A Th2 response, which is characterized by the release of interleukin-4 (IL-4), leads to the responses mediated by macromolecules found in extracellular fluids such as secreted antibodies, complement proteins and certain antimicrobial peptides.
The immune system also provides for immune suppression to limit the damaging potential of an immune response. The immunosuppressive regulatory T cell sub-population of T cells attenuates a cytotoxic T cell response, and normally protects against over-stimulation and development of autoimmunity. Even prior to differentiation into naïve T cells, a group of T cell precursors differentiate into natural regulatory T cells in the thymus by moderate interaction with the self-peptide MHC complex. Regulatory T cells also include inducible regulatory T cells developed from CD4+ T cells outside of the thymus. Whereas natural regulatory T cells suppress T cell activation by interaction with antigen-presenting cells to produce negative signals for T cell activation, inducible regulatory T cells produce cytokines that inhibit T cell proliferation.
Imbalance between the active and suppressive immune response can result in diseases and conditions such as cancer, immunodeficiency (e.g., acquired immunodeficiency syndrome), autoimmune diseases, or hypersensitivity reactions or worsen diseases and infections, for example, tuberculosis, Leishmania, or malaria.
As immune cells patrol the body for potential dangers, immune cells also eliminate tumors. A strong, anti-cancer immune response requires antibodies (the adaptive, humoral arm) and an active cell-mediated arm. The interplay between these two arms is driven by activation of dendritic cells (the primary antigen-presenting cell type, APCs) and subsequent production of antibodies by B cells. Destruction of cancer cells then occurs by two processes: a cytotoxic cellular response by neutrophils, natural killer cells, cytotoxic T cells, and macrophages, and an antibody-dependent cellular cytotoxicity (ADCC) performed by activated macrophages and neutrophils. Often tumor cells can be made more susceptible to digestion for antigen presentation by radiation treatment or chemotherapy. Activation of these cells provides a multi-pronged approach that should overcome immune suppression or “evasion of immune destruction,” a major hallmark of cancer [Hanahan and Weinberg, 2011]. Whereas Hanahan and Weinberg support the ‘somatic mutation theory’ for the origin of cancer, Sonnenschein et al. (2014) provided an alternate proposal that cancer results from a breakdown of tissue organization, or the ‘tissue organization field theory.”
A goal of immunotherapy is to restore the ability of the immune system to overcome these diseases. Traditional immunotherapy targets have been antigens specific to the targeted cells, such as tumor-associated antigens (e.g., Tn antigen or Tf antigen) or glycosylation groups expressed on the surface of viruses or bacteria or on cells infected by the viruses or bacteria. For example, vaccinations using these antigens induce endogenous production of antibodies against these antigens to mount an immune response. The traditional approach also uses adjuvants to aid the stimulation of the immune system, but greater understanding of immune responses have expanded the potential candidates for factors that activate immune cells to stimulate the immune system either directly or indirectly to mount an immune response. Understanding of immune checkpoints has enabled immunotherapy to target proteins involved in regulating the balance of the immune response, for example, to suppress or enhance the population of regulatory T cells. Thus immunotherapy is now able to 1) induce endogenous production of antibodies, 2) provide exogenous antibodies that manipulate the type of immune response to be mounted, and 3) activate or suppress specific immune cells by factors from the immune system checkpoint.
The present invention is directed to combinations of these approaches for improved immunotherapy, for example, to boost the immunogenicity of tumors. In particular, the present invention is directed to the use of peptides in combination with antibodies, such as exogenous antibodies against immune checkpoint proteins or against cancer markers. Peptides that mimic sugars and bind to regulatory lectin-type receptors expressed by key cells of the immune system can enhance the immune responses, which can support the therapeutic benefits of the exogenous antibodies.